Chronic pain represents a major unmet clinical need. Studies in our lab are designed to identify molecular mechanisms of sensitization in pain pathways with the goal of identifying novel targets for analgesic intervention. Studies performed under the two previous terms of this grant identified a critical signaling cascade in spinal cord dorsal horn neurons that underlies central pain sensitization. This pathway is initiated by mGlu5 activation of extracellular signal-regulated kinase (ERK1/2) signaling, leading to phosphorylation of a Kv4.2- containing K+ channels, resulting in enhanced excitability of dorsal horn neurons. This increase in excitability likely contributes to central sensitization associated with persistent pain. The studies proposed here will test whether modulation of neuronal excitability and nociceptive behaviors by mGlu5 requires ERK2 (and not ERK1), and whether this is a direct result of phosphorylation of Kv4.2 at a functionally identified phosphorylation site. We will also test the potential clinical utility of fenobam, a clinically validated selective mGlu5 antagonist. We will initially test whether tolerance to the analgesic actions of this drug develops with repeated dosing. Finally, we will take our findings of a key role for mGlu5 in central pain sensitization from the laboratory to the clinic by initiating human trials and asking whether an mGlu5 antagonist can reverse central sensitization in healthy volunteers.